Polypeptide hormones such as insulin, calcitonin, and the like are a water-soluble high molecular weight compound which is easily decomposed by gastric juice or a protease such as pepsin, trypsin, and the like. Accordingly, when these polypeptide are orally administered, they are almost decomposed without being absorbed and hence, they hardly show the effective physiological activity thereof. Therefore, at present, the pharmaceutical composition of these polypeptides are usually prepared in a suitable form for injection in order to obtain the desired biological activity thereof. However, when the polypeptides need to be administered at regular intervals and repeatedly, the injection route is inconvenient and painful for patients, and hence, recent attention has been given to efforts for developing other administration methods for polypeptides instead of by the injection route.
A pharmaceutical composition for administration into the nasal cavity, the vagina or the rectum has been disclosed in Hirai et al., U.S. Pat. No. 4,659,696 and Uda et al., U.S. Pat. No. 4,670,419, which comprises a hydrophilic drug which is hardly absorbed in the gastrointestinal tract and cyclodextrin. The hydrophilic drug used in the said pharmaceutical composition includes polypeptides such as insulin, LH-RH analogue, oxytocin, TRH, and the like. The cyclodextrin used in this pharmaceutical preparation is preferably .alpha.-cyclodextrin. Various additives are also contained in said composition.
Further, a pharmaceutical composition for administration into the rectum or the vagina is disclosed in Morishita et al., U.S. Pat. No. 4,609,640, which comprises a water-soluble drug and a specific type water-soluble chelating agent and will show excellent absorbability of the drug. The water-soluble drug used in the said pharmaceutical composition includes polypeptides such as insulin, somatostatin, calcitonin, and the like. When a chelating agent with low molecular weight such as a polycarboxylic acid is used together, a water-soluble high molecular weight base which does not have chelating activity, for example, gelatin, casein, albumin, globulin is also used. Other conventional additives which are necessary for these administration dosage forms, for example, a surfactant, may also be contained therein.
Moreover, a transnasal powder preparation is disclosed in European Patent Publication EP-A-0193372, which comprises a physiologically active polypeptide, a quaternary ammonium compound and a lower alkyl ether of cellulose, which will have excellent preservability and chemical stability. The preferred powder preparation comprises insulin or calcitonin, benzalkonium chloride and hydroxypropyl cellulose. Various conventional additives, for example, lubricants, waxes, binding agents, diluents, colorants, flavoring agents, antioxidants, fillers, isotonic agents, surfactants, and the like are also contained therein.
Further, an absorbable intranasal preparation of calcitonin is disclosed in European Patent Publication EP-A-0183527, which comprises a calcitonin and at least one absorption promoter selected from the group consisting of acids or a salt thereof, benzilic acid or a salt thereof, capric acid or a salt thereof, polyethylene glycol 400, pyridoxal or a salt thereof, malic acid or a salt thereof and pyrophosphoric acid or a salt thereof. Other conventional additives for intranasal preparations may be added thereto. It is thought that by using one of these specific absorption promoters, the efficiency of absorbing through the nasal cavity membrane is improved. The above mentioned patent application says that a surfactant had been used as an absorption promoter in order to improve the absorbability through the nasal cavity of a large polypeptide such as calcitonin in the beginning. Both amphoteric and cationic surfactants, especially nonionic surfactant, polyoxyethylenelauryl ether had been used in the early studies. However, it is assumed that such a desirable ether-type surfactant enhances the absorbability of a medicament by destroying the nasal cavity membrane.
British Patent Application No. 8326436 which is published under GB-2127689A discloses an intranasal preparation, which comprises calcitonin incorporated into a suitable liquid diluent or carrier for administration into nasal cavity mucous membrane, benzalkonium chloride and/or a surfactant being suitable for administration into the nasal cavity. When the said preparation contains a surfactant, the surfactant is preferably a nonionic surfactant, more preferably polyoxyalkylene higher alcohol ether. It is reported that by these transnasal preparations of calcitonin, the bioavailability of calcitonin and the stability thereof are improved.
Moreover, a pharmaceutical composition of LH-RH or an analogue thereof for administration into the rectum or the vagina is disclosed in Matsuzawa et al. U.S. Pat. No. 3,917,825. In the said composition, it is preferable that nonapeptide or decapeptide is uniformly dispersed into an oil base (e.q. oil, wax or fatty acid triglyceride) containing a nonionic surfactant such as polyoxyethylene higher alcohol ether, and the like. Various administration methods including the transvaginal route of the nonapeptide or decapeptide are disclosed in numerous patent applications and patent publications such as Beddell et al., U.S. Pat. No. 4,083,967, Immer et al., U.S. Pat. No. 3,888,838, Nestor et al., U.S. Pat. No. 4,234,571, Schally et al., U.S. Pat. Nos. 4,010,125 and 4,018,726, and Saito et al., Fertility and Sterility, Vol. 28, No. 3, March 1977, 240-245.
Further, there is disclosed potent transvaginal adsorption of LH-RH analogue (leuprolide), LH-RH itself, and insulin in Okada et al., J. Pharm. Sci., Vol. 72, No. 1, January 1983, 75-78. The increase in absorbability thereof is obtained by using an organic acid. The enhancing effect on the absorbability seems to correlate with the chelation property of the organic acid to be used [cf. Okada et al., J. Takeda Res. Lab. 42 (1/2), 150 (1983)].
Touitou et al. developed a hydrophilic preparation for administration into the rectum or the vagina of insulin, heparin, phenol red and gentamicin which comprises as an nonionic surfactant polyethylene glycol together with cetomacrogol 1000 (polyethylene glycol 1000 monocetyl ether) (cf. J. Pharm. Pharmac., 1978, 30, 663). IL 54041 of the Jerusalem University seems to relate to the similar study to the above, which discloses an enteric coated preparation and a transvaginal preparation of peptide hormone or heparin containing a nonionic surfactant.
Morimoto et al. reported in J. Pharm. Pharmacol. 1985, 37, 759-760 the effect of nonionic surfactants, polyoxyethylene sorbitan monooleate and polyoxyethylene(9)lauryl ether, and the absorption promoting property of polyacrylic acid gel base on the adsorption at the rectum of semi-synthesized analogue of eel calcitonin. It was discovered at the early stage that polyacrylic acid gel base improves the absorption of insulin administered into the rectum, the vagina and the nasal cavity, and also the adsorption of calcitonin administered into the rectum or the nasal cavity. The early report indicates that the absorbability of hardly absorbable drug is improved by administering thereof together with enamine, carboxylic acid and a surfactant.
There is disclosed an intrarectal preparation of calcitonin in Japanese Patent Publication No. 56-122309, wherein calcitonin and a surfactant (e.g. cholic acid, saponin, phospholipid, polyoxyethylenealkyl ether, glycerin fatty acid ester, sorbitan fatty acid ester, etc.) are dispersed uniformly in a suppository base.
Moreover, there is disclosed absorption in the intestine of a drug by various compositions which promote absorption of a drug to be absorbed through the cell lining on the surface of the mucous membrane in Muranishi, S., "Absorption Barriers and Absorption Promoters in the Intestine" of Topics in Pharmaceutical Sciences, 1987. A mixed micelle is also disclosed therein, wherein a nonionic surfactant and an unsaturated aliphatic carboxylic acid are used.
Although there are many studies on the administration methods of polypeptides as mentioned above, these methods generally still have numerous defects. That is, when a drug is administered by one of above mentioned methods, it is necessary to administer the drug at a-higher dose thereof than when it is administered by the injection route. As a result, the absorbed amount of the drug fluctuates widely. Thus, it is desirable that dosage forms for a polypeptide are excellent in the storage stability, and the polypeptide therein is easily absorbed without stimulating the mucous membrane of the administered region, and stable at the administered region. Hitherto, although there have been many attempts to discover an alternative administration method of a biologically active polypeptide such as insulin, calcitonin and the like instead of by the conventional injection route, no attention has been given to the problem that the biologically active polypeptide tends to lose biological activity during storage. The requisite to obtain a stable pharmaceutical dosage form containing a biologically active polypeptide is important for preparing the above pharmaceutical compositions. Moreover, in the study on the alternatives to the injection route, the above mentioned prior arts do not suggest the way to avoid the enzymolysis of polypeptide which occurs during the process of absorption at the administered region.